An oral STING inhibitor that blocks palmitoylation shows efficacy in inflammation models
- Researchers built a tetrahydropyrazolo[1,5-a]pyrazine series as inhibitors of STING, the innate-immune adaptor behind several interferonopathies and autoimmune conditions.
- The lead, compound 37, combined strong cellular STING inhibition with good oral exposure and a clean safety read.
- Mechanistically it prevents STING palmitoylation, which in turn shuts down downstream signaling.
- Oral dosing reduced inflammation in acute chemical-challenge and Trex1-deficient mouse models, among others.
💡 Points
STING inhibitors have mostly been tool compounds or covalent binders, so a non-covalent-looking, orally dosed chemotype that acts by blocking palmitoylation is a different handle on the target. I would want to know whether it truly binds the Cys91 pocket or acts upstream, because that decides selectivity versus other palmitoylated proteins. The Trex1 mouse data is the convincing part for an autoimmune indication.